Skipping ahead: A circuit for representing the past, present, and future

Envisioning the future is intuitively linked to our ability to remember the past. Within the memory system, substantial work has demonstrated the involvement of the prefrontal cortex and the hippocampus in representing the past and present. Recent data shows that both the prefrontal cortex and the hippocampus encode future trajectories, which are segregated in time by alternating cycles of the theta rhythm. Here, we discuss how information is temporally organized by these brain regions supported by the medial septum, nucleus reuniens, and parahippocampal regions. Finally, we highlight a brain circuit that we predict is essential for the temporal segregation of future scenarios.

Nucleus Reuniens Afferents in Hippocampus Modulate CA1 Network Function via Monosynaptic Excitation and Polysynaptic Inhibition

The thalamic midline nucleus reuniens modulates hippocampal CA1 and subiculum function via dense projections to the stratum lacunosum-moleculare (SLM). Previously, anatomical data has shown that reuniens inputs in the SLM form synapses with dendrites of both CA1 principal cells and inhibitory interneurons. However, the ability of thalamic inputs to excite the CA1 principal cells remains controversial. In addition, nothing is known about the impact of reuniens inputs on diverse subpopulations of interneurons in CA1. Therefore, using whole cell patch-clamp electrophysiology in ex vivo hippocampal slices of wild-type and transgenic mice, we measured synaptic responses in different CA1 neuronal subtypes to optogenetic stimulation of reuniens afferents. Our data shows that reuniens inputs mediate both excitation and inhibition of the CA1 principal cells. However, the optogenetic excitation of the reuniens inputs failed to drive action potential firing in the majority of the principal cells. While the excitatory postsynaptic currents were mediated via direct monosynaptic activation of the CA1 principal cells, the inhibitory postsynaptic currents were generated polysynaptically via activation of local GABAergic interneurons. Moreover, we demonstrate that optogenetic stimulation of reuniens inputs differentially recruit at least two distinct and non-overlapping subpopulations of local GABAergic interneurons in CA1. We show that neurogliaform cells located in SLM, and calretinin-containing interneuron-selective interneurons at the SLM/stratum radiatum border can be excited by stimulation of reuniens inputs. Together, our data demonstrate that optogenetic stimulation of reuniens afferents can mediate excitation, feedforward inhibition, and disinhibition of the postsynaptic CA1 principal cells via multiple direct and indirect mechanisms.

Dual medial prefrontal cortex and hippocampus projecting neurons in the paraventricular nucleus of the thalamus

The paraventricular nucleus (PVT) of the midline thalamus is a critical higher-order cortico-thalamo-cortical integration site that plays a critical role in various behaviors including reward seeking, cue saliency, and emotional memory. Anatomical studies have shown that PVT projects to both medial prefrontal cortex (mPFC) and hippocampus (HC). However, dual mPFC-HC projecting neurons which could serve a role in synchronizing mPFC and HC activity during PVT-dependent behaviors, have not been explored. Here we used a dual retrograde adenoassociated virus (AAV) tracing approach to characterize the location and proportion of different projection populations that send collaterals to mPFC and/or ventral hippocampus (vHC). Additionally, we examined the distribution of calcium binding proteins calretinin (CR) and calbindin (CB) with respect to these projection populations PVT. We found that PVT contains separate populations of cells that project to mPFC, vHC, and those that innervate both regions. Interestingly, dual mPFC-HC projecting cells expressed neither CR or CB. Topographically, mPFC- and vHC-projecting CB+ and CR+ cells clustered around dual projecting neurons in PVT. These results are consistent with the features of dual mPFC-vHC projecting cells in the nucleus reuniens (RE) and suggestive of a functional mPFC-PVT-vHC system that may support mPFC-vHC interactions in PVT-dependent behaviors.

Hippocampal CA1 pyramidal cells do not receive monosynaptic input from thalamic nucleus reuniens

Midline thalamic nuclei play a critical role in cognitive functions such as memory, decision-making and spatial navigation, by facilitating communication between the many brain regions involved in these processes. One canonical feature of thalamic interactions with the cortex or hippocampus appears to be that the thalamus receives input from, and projects to, excitatory neurons. Thalamic nucleus reuniens (NRe) is located on the midline and is viewed primarily as a relay from prefrontal cortex to hippocampal and entorhinal areas, although these connections are poorly defined at the cellular and synaptic level. Using electrophysiology and monosynaptic circuit-tracing, we found that pyramidal cells in CA1 receive no direct input from NRe. This contrasts starkly with prefrontal cortex, subiculum and entorhinal cortex, and indicates that NRe inputs to CA1 primarily drive local inhibition and not excitation they do in the other regions. The NRe to CA1 projection is thus a unique thalamic projection and as such is raising important questions about the function of NRe-mediated prefrontal control of the hippocampus.

Encoding and retrieval of associative recognition memory engage different sub-networks within a hippocampal-thalamo-cortical memory circuit

Recognition of previously encountered stimuli and their associated spatial and temporal information depends on neural activity within a brain-wide network in which the CA1 region of the hippocampus, nucleus reuniens of the thalamus (NRe) and medial prefrontal cortex (mPFC) are key nodes. However, the pathways crucial for coordinating activity during memory encoding and/or retrieval phases have been little explored. Here we opto- or chemo associative recognition memory. We discovered that encoding, but not retrieval depended on the CA1 to mPFC and NRe to mPFC projections. In contrast, retrieval depended on the mPFC to NRe projection. Interestingly the NRe to CA1 pathway was required for both memory phases. Our findings therefore reveal that encoding and retrieval engage dissociable sub-networks within a hippocampal-thalamo-cortical recognition memory circuit in order to enable binding of recent and related information, whilst ensuring a separation of processing.

Thalamo-hippocampal pathway regulates incidental memory load: insights from sex differences

Memory can be challenged by increasing both its required duration and the amount of information to be encoded, namely the memory load. The dorsal hippocampus (dHP) has been involved in memory consolidation, which is the stabilization of a trace from short-term (STM) to long-term memory (LTM), as well as in the ability to process high information load. However, how memory load influences memory consolidation, and the underlying neural mechanisms, are yet unknown. To address this question, we used male and female mice that, despite having in our Different Object recognition Task (DOT) the same STM capacity of 6 objects, spontaneously show differences in the number of objects directly transferred to LTM, when tested over longer delays. Males memorize all 6 objects encoded, while females remember only up to 4, both at 1 and 24 h delays. Interestingly, males activate more the dHP (as measured by c-Fos expression), while females the thalamic nucleus reuniens (RE). Optogenetic inhibition of the RE-dHP pathway during off-line memory consolidation favors 6-object LTM retention in females by removing inhibitory control over dHP activation, while chemogenetic RE-activation impairs it in males. Our data represent a first demonstration of a sub-cortical control of dHP recruitment, that might underlie its sex-dependent activation during incidental memory, with potential also for clinical application.